ADH-10001(ADH-10001) - 药物靶点：CDH2_专利_临床

概要

基本信息

药物类型

合成多肽

别名

Exherin、ADH 1、ADH-1

+ [1]

靶点

CDH2

作用方式

抑制剂

作用机制

CDH2抑制剂(钙粘蛋白-2抑制剂)、血管生成抑制剂

治疗领域

肿瘤皮肤和肌肉骨骼疾病消化系统疾病+ [2]

在研适应症-

非在研适应症

Vater壶腹癌胆囊腺癌肝内胆管癌+ [4]

原研机构

McGill-Queen's University Press

在研机构-

非在研机构

Fennec Pharmaceuticals, Inc.

权益机构

Fennec Pharmaceuticals, Inc.Elion Oncology, Inc.

最高研发阶段无进展临床2期

首次获批日期-

最高研发阶段(中国)-

特殊审评-

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结构/序列

分子式C22H34N8O6S2

InChIKeyFQVLRGLGWNWPSS-BXBUPLCLSA-N

CAS号229971-81-7

Sequence Code 33854749

关联

6

项与 ADH-10001 相关的临床试验

NCT01825603

/ Completed临床1期IIT

A Phase I Study of ADH-1 and Gemcitabine Plus Cisplatin in Patients With Unresectable or Metastatic Pancreatic and Biliary Tract Cancers

This phase I trial studies the side effects and best dose of ADH-1 when given together with gemcitabine hydrochloride and cisplatin in treating patients with pancreatic or biliary tract cancer that has spread from where it started to nearby tissue or lymph nodes (locally advanced) or spread to other parts of the body (metastatic) and cannot be removed by surgery. ADH-1 may stop the growth of cancer cells by blocking blood flow to the tumor. Drugs used in chemotherapy, such as gemcitabine hydrochloride and cisplatin, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving ADH-1 together with gemcitabine hydrochloride and cisplatin may kill more tumor cells.

开始日期2013-04-09

申办/合作机构

University of Nebraska

[+2]

NCT00421811

/ Completed临床1/2期

An Open-Label, Multicenter, Phase 1/2 Dose Escalation Study to Evaluate Safety, Tolerability and Anti-tumor Activity of Systemic ADH-1 in Combination With Normothermic Isolated Limb Infusion of Melphalan in Subjects With Locally Advanced In-Transit Malignant Melanoma (Adherex Protocol Number AHX-01-007).

N-cadherin, a protein involved in blood vessel cell binding and on the surface of many tumor cells, is increased as cancer progresses. ADH-1 blocks N-cadherin. This study will test the safety and effects of the combination ADH-1 with Normothermic Isolated Limb Infusion of Melphalan in subjects with locally advanced malignant melanoma.

开始日期2007-04-01

申办/合作机构

Fennec Pharmaceuticals, Inc.

NCT00390676

/ Completed临床1期

A Phase 1, Multicenter, Dose-Escalation Study to Investigate the Safety and Tolerability of ADH-1 in Combination With 1) Carboplatin or 2) Docetaxel or 3) Capecitabine in Subjects With N-Cadherin Positive, Advanced Solid Tumors (Adherex Protocol Number AHX-01-006)

N-cadherin, a protein involved in blood vessel cell binding, is increased as cancer progresses, and is on the surface of many tumor cells. ADH-1 blocks N-cadherin. This study will test the safety and effects of the combination ADH-1 and carboplatin or ADH-1 and docetaxel or ADH-1 and capecitabine in subjects with specific incurable, solid tumors with a protein biomarker called N-cadherin.

开始日期2006-11-01

申办/合作机构

Fennec Pharmaceuticals, Inc.

[+1]

100 项与 ADH-10001 相关的临床结果

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100 项与 ADH-10001 相关的转化医学

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100 项与 ADH-10001 相关的专利（医药）

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111

项与 ADH-10001 相关的文献（医药）

2023-02-01·iScience

Low-dose ethanol increases aflatoxin production due to the adh1-dependent incorporation of ethanol into aflatoxin biosynthesis

Article

作者: Enomoto, Hirofumi ; Kushiro, Masayo ; Sakuda, Shohei ; Furukawa, Tomohiro ; Nakagawa, Hiroyuki

Aflatoxins are toxic secondary metabolites produced by some aspergilli, including Aspergillus flavus. Recently, ethanol has attracted attention as an agent for the control of aflatoxin contamination. However, as aflatoxin biosynthesis utilizes acetyl coenzyme A, ethanol may be conversely exploited for aflatoxin production. Here, we demonstrated that not only the ¹³C of labeled ethanol, but also that of labeled 2-propanol, was incorporated into aflatoxin B₁ and B₂, and that ethanol and 2-propanol upregulated aflatoxin production at low concentrations (<1% and <0.6%, respectively). In the alcohol dehydrogenase gene adh1 deletion mutant, the ¹³C incorporation of labeled ethanol, but not labeled 2-propanol, into aflatoxin B₁ and B₂ was attenuated, indicating that the alcohols have different utilization pathways. Our results show that A. flavus utilizes ethanol and 2-propanol as carbon sources for aflatoxin biosynthesis and that adh1 indirectly controls aflatoxin production by balancing ethanol production and catabolism.

2023-01-02·Molecular and cellular biology

Sumoylation is Largely Dispensable for Normal Growth but Facilitates Heat Tolerance in Yeast

Article

作者: McNeil, J. Bryan ; Baig, Mohammad S. ; Moallem, Marjan ; Burke, Giovanni L. ; Babu, John ; Akhter, Akhi ; Bergey, Benjamin G. ; Rosonina, Emanuel

Numerous proteins are sumoylated in normally growing yeast and SUMO conjugation levels rise upon exposure to several stress conditions. We observe high levels of sumoylation also during early exponential growth and when nutrient-rich medium is used. However, we find that reduced sumoylation (∼75% less than normal) is remarkably well-tolerated, with no apparent growth defects under nonstress conditions or under osmotic, oxidative, or ethanol stresses. In contrast, strains with reduced activity of Ubc9, the sole SUMO conjugase, are temperature-sensitive, implicating sumoylation in the heat stress response, specifically. Aligned with this, a mild heat shock triggers increased sumoylation which requires functional levels of Ubc9, but likely also depends on decreased desumoylation, since heat shock reduces protein levels of Ulp1, the major SUMO protease. Furthermore, we find that a ubc9 mutant strain with only ∼5% of normal sumoylation levels shows a modest growth defect, has abnormal genomic distribution of RNA polymerase II (RNAPII), and displays a greatly expanded redistribution of RNAPII after heat shock. Together, our data implies that SUMO conjugations are largely dispensable under normal conditions, but a threshold level of Ubc9 activity is needed to maintain transcriptional control and to modulate the redistribution of RNAPII and promote survival when temperatures rise.

2023-01-01·Frontiers in oncology

[¹⁸F]AlF-NOTA-ADH-1: A new PET molecular radiotracer for imaging of N-cadherin-positive tumors.

Article

作者: Wang, GuoLin ; Wen, Guanghua ; Liu, Zhenfeng ; Dong, Mengjie ; Huang, Yuqiao ; Wang, Zewei ; Lu, Hui ; Alhaskawi, Ahmad ; Dong, Yanzhao ; Ye, Qianni ; Zhou, Haiying ; Zhang, Shuyi

Background:

The cell adhesion molecule (CAM) N-cadherin has become an important target for tumor therapy. The N-cadherin antagonist, ADH-1, exerts significant antitumor activity against N-cadherin-expressing cancers.

Methods:

In this study, [¹⁸F]AlF-NOTA-ADH-1 was radiosynthesized. An in vitro cell binding test was performed, and the biodistribution and micro-PET imaging of the probe targeting N-cadherin were also studied in vivo.

Results:

Radiolabeling of ADH-1 with [¹⁸F]AlF achieved a yield of up to 30% (not decay-corrected) with a radiochemical purity of >97%. The cell uptake study showed that Cy3-ADH-1 binds to SW480 cells but weakly binds to BXPC3 cells in the same concentration range. The biodistribution results demonstrated that [¹⁸F]AlF-NOTA-ADH-1 had a good tumor/muscle ratio (8.70±2.68) in patient-derived xenograft (PDX) tumor xenografts but a lower tumor/muscle ratio (1.91±0.69) in SW480 tumor xenografts and lowest tumor/muscle ratio (0.96±0.32) in BXPC3 tumor xenografts at 1 h post-injection (p.i.) These findings were in accordance with the immunohistochemistry results. The micro PET imaging results revealed good [18F]AlF-NOTA-ADH-1 tumor uptake in pancreatic cancer PDX xenografts with strong positive N-calcium expression, while lower tumor uptake in SW480 xenografts with positive expression of N-cadherin, and significantly lower tumor uptake in BXPC3 xenografts with low expression of N-cadherin, which was consistent with the biodistribution and immunohistochemistry results. The N-cadherin-specific binding of [18F]AlF-NOTA-ADH-1 was further verified by a blocking experiment involving coinjection of a non radiolabeled ADH-1 peptide, resulting in a significant reduction in tumor uptake in PDX xenografts and SW480 tumor.

Conclusion:

[¹⁸F]AlF-NOTA-ADH-1 was successfully radiosynthesized, and Cy3-ADH-1 showed favorable N-cadherin-specific targeting ability by in vitro data. The biodistribution and microPET imaging of the probe further showed that [18F]AlF-NOTA-ADH-1 could discern different expressions of N-cadherin in tumors. Collectively, the findings demonstrated the potential of [¹⁸F]AlF-NOTA-ADH-1 as a PET imaging probe for non-invasive evaluation of the N-cadherin expression in tumors.

1

项与 ADH-10001 相关的新闻（医药）

2023-02-28

·生物谷

Cell子刊：这个负责酒精代谢的基因，有助于延长寿命

这项研究发现，与酒量相关的酒精脱氢酶ADH-1是促进长寿的下游效应物，其激活足以延长从酵母到人类的健康寿命和最终寿命。这提示我们，ADH-1可能是一个十分重要的抗衰老干预靶点众所周知，喝酒有害健康，许多研究表明，酒精（乙醇）是一种致癌物，喝酒与包括癌症在内的一系列伤害和疾病有关。我们在喝酒后，酒精进入体内，首先被肝脏中的乙醇脱氢酶（ADH）转化为乙醛，乙醛被乙醛脱氢酶（ALDH）转化为乙酸，乙酸最终被转化为二氧化碳和水。通常情况下，人们的ADH酶活性相差不大，而ALDH酶活性则差别较大，因此，ALDH活性是酒量主要决定因素。增加ALDH酶活性能够加速酒精代谢的有毒的中间产物乙醛的转化，减少饮酒对身体的伤害。那么，增加ADH酶活性会有什么益处呢？一项最新研究显示，增加乙醇脱氢酶1（ADH-1）活性可延长寿命。近日，美国弗吉尼亚大学的研究人员在 Cell 子刊 Current Biology 上发表题为：Increased alcohol dehydrogenase 1 activity promotes longevity（增加乙醇脱氢酶1活性可延长寿命）的研究论文。该研究发现了由乙醇脱氢酶（ADH）介导的抗衰老反应（简称AMAR），这种酒精代谢相关的酶在多种长寿秀丽隐杆线虫模型中被激活，并且是长寿表型所必须的。不仅如此，ADH-1同源物在禁食小鼠和人类（多项研究表明禁食促进长寿）中同样被诱导，表明ADH-1在广泛的物种中发挥抗衰老效应。这项研究提示我们，ADH-1可能是一个十分重要的抗衰老干预靶点，可以之为核心开发全新的抗衰老疗法。近年来，全球老龄化程度加剧，抗衰老研究成为了世界生命科学领域关注的前沿和热点。在过去的几十年里，科学家们一直在努力破解人类衰老的秘密，与衰老相关的信号分子被相继发现，并以此衍生了多种抗衰老疗法。然而，这些衰老相关因子大多是上游信号枢纽（如mTOR）或中间转录因子（如FOXO/DAF-16），目前尚不清楚是否有下游效应物对长寿是必要且充分的。具有强大抗衰老作用的下游效应物有助于揭示决定衰老速度的基本机制，并且可能是更安全、更有效的抗衰老靶标。发掘这种长寿的下游效应物的一个十分有吸引力的方法是研究在多种促长寿条件下负责激活抗衰老程序的转录因子（TFs），其中一个突出的抗衰老TF是转录因子EB（TFEB）。在研究衰老的模式生物——秀丽隐杆线虫（C. elegans）中，TFEB的同源物为HLH-30。多项研究显示，激活HLH-30可以延长线虫寿命并减少衰老相关的生物标志物。此外，有研究表明，作为自噬和溶酶体生物发生的主要调节因子，HLH-30通过激活自噬来延长健康和寿命，而自噬被认为是生物体长寿所普遍必须的。在这项最新研究中，研究团队在mxl-3突变的长寿线虫模型（以下简称：mxl-3线虫）发现了与上述研究不同的新现象：由mxl-3驱动的长寿需要HLH-30的活性，而HLH-30是自噬的主要调节因子，研究团队首先假设HLH-30通过激活自噬促进了mxl-3线虫的长寿。但与预期相反，研究团队发现自噬在mxl-3线虫中没有被激活。在这些拥有长寿表型的mxl-3线虫中，自噬和溶酶体活性都不是必需的。简而言之，mxl-3线虫的寿命依赖于HLH-30，但不依赖于自噬。 ADH-1对于延长寿命和健康寿命是必要和充分的与此同时，研究团队意外地发现，编码酒精脱氢酶ADH-1的基因在mxl-3线虫和其他依赖于HLH-30的长寿线虫模型中被诱导，包括热量限制（eat-2突变体）、胰岛素信号缺乏（daf-2缺陷）和生长受限（mTOR抑制）。更重要的是，ADH-1基因对于所有这些抗衰老干预的长寿表型都是必要的，并且过表达ADH-1就足以延长秀丽隐杆线虫的寿命。进一步的研究表明，ADH-1通过代谢有毒的甘油来延长寿命，这种有害物质会随着年龄的增长而不断积累。 ADH-1通过阻止促进衰老的代谢物甘油的积累来延长寿命最后，研究团队还提出证据表明，ADH-1的抗衰老能力可能在物种之间是高度保守的，具有从低等生物到高等动物的广泛性。例如，ADH-1过表达也可以延长酵母的寿命，ADH-1直系同源物在热量受限的小鼠和人类中同样被诱导。 ADH-1在热量限制下被诱导激活，并足以延长酵母的寿命总而言之，这项研究发现，与酒量相关的酒精脱氢酶ADH-1是促进长寿的下游效应物，其激活足以延长从酵母到人类的健康寿命和最终寿命。这提示我们，ADH-1可能是一个十分重要的抗衰老干预靶点，可以以之为核心开发全新的抗衰老疗法。

100 项与 ADH-10001 相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
-	ADH-10001	-	DB05485

研发状态

10 条进展最快的记录,

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适应症	最高研发状态	国家/地区	公司	日期
局部晚期黑色素瘤	临床2期	美国	Fennec Pharmaceuticals, Inc.	2007-04-01
实体瘤	临床2期	意大利	Fennec Pharmaceuticals, Inc.	2005-06-01
实体瘤	临床2期	瑞士	Fennec Pharmaceuticals, Inc.	2005-06-01
Vater壶腹癌	临床1期	美国	Fennec Pharmaceuticals, Inc.	2013-04-09
胆囊腺癌	临床1期	美国	Fennec Pharmaceuticals, Inc.	2013-04-09
肝内胆管癌	临床1期	美国	Fennec Pharmaceuticals, Inc.	2013-04-09
克拉茨金瘤	临床1期	美国	Fennec Pharmaceuticals, Inc.	2013-04-09
转移性胰腺腺癌	临床1期	美国	Fennec Pharmaceuticals, Inc.	2013-04-09

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临床结果

适应症

分期

评价

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT01825603 (ASCO_GI2017)	临床1期	胆道癌 \| 胰腺癌	17	ADH-1	鑰鑰築壓願獵遞遞製積(憲艱壓廠構糧餘鏇簾鏇) = 憲憲構齋蓋艱製積構鹽衊築獵糧壓積齋製顧齋 (鏇蓋願觸製鬱醖構窪積 ) 更多	-	2017-03-21
ASCO2008	临床1期	实体瘤	35	ADH-1	選膚繭襯製膚醖遞範衊(選積鹽顧窪廠鑰觸願艱) = 壓衊廠遞廠糧築襯鏇齋築觸簾淵製廠簾齋夢網 (鑰醖廠鹽壓醖憲鑰積範 )	-	2008-05-20
ASCO2008	临床1期	实体瘤	35	Docetaxel	壓餘構廠範築鹹襯鏇膚(繭構蓋選艱衊壓鑰餘窪) = 構構衊築顧鹹鬱鬱壓餘鹹蓋構積鏇顧憲簾衊憲 (壓鏇齋製壓製糧窪獵積 )	-	2008-05-20
ASCO2008	临床1/2期	局部晚期黑色素瘤	11	Systemic ADH-1	築襯製觸壓憲膚餘膚壓(範蓋鑰膚餘觸廠餘鹽獵) = 鏇鑰蓋遞淵艱鏇網廠製鹹艱鬱齋構餘廠簾鏇觸 (淵糧積鏇製選顧顧壓艱 )	-	2008-05-20
ASCO2007	临床2期	实体瘤	-	ADH-1 500 mg/m2 q 3 W	製糧製壓襯製鑰餘衊鬱(夢窪觸窪蓋壓衊鹽蓋簾) = 糧觸觸網選觸窪餘鑰齋夢糧廠醖選餘願膚獵夢 (顧網鏇網夢廠壓齋鹹遞 ) 更多	-	2007-06-20
ASCO2007	临床2期	实体瘤	-	ADH-1 600 mg/m2 qW	製糧製壓襯製鑰餘衊鬱(夢窪觸窪蓋壓衊鹽蓋簾) = 鬱餘簾夢願廠積壓簾夢夢糧廠醖選餘願膚獵夢 (顧網鏇網夢廠壓齋鹹遞 ) 更多	-	2007-06-20
ASCO2005	临床1期	实体瘤	33	ADH-1	壓壓顧鹽願膚製膚願網(積繭範願築膚鹽壓鏇繭) = 糧壓膚願製簾鹹觸蓋壓繭製範簾廠蓋選淵構製 (淵壓築積齋憲構衊選範 )	积极	2005-06-01